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Genetic Variants in RUNX3, AMD1 and MSRA in the Methionine Metabolic Pathway and Survival in Non-small Cell Lung Cancer Patients.

dc.contributor.author Moorman, Patricia
dc.contributor.author Luo, Sheng
dc.contributor.author Wei, Qingyi
dc.contributor.author Chen, Ka
dc.contributor.author Liu, Hongliang
dc.contributor.author Liu, Zhensheng
dc.contributor.author Patz, Edward F
dc.contributor.author Su, Li
dc.contributor.author Shen, Sipeng
dc.contributor.author Christiani, David C
dc.date.accessioned 2019-02-01T14:40:24Z
dc.date.available 2019-02-01T14:40:24Z
dc.date.issued 2019-01-16
dc.identifier.issn 0020-7136
dc.identifier.issn 1097-0215
dc.identifier.uri https://hdl.handle.net/10161/17935
dc.description.abstract Abnormal methionine dependence in cancer cells has led to methionine restriction as a potential therapeutic strategy. We hypothesized that genetic variants involved in methionine-metabolic genes are associated with survival in non-small cell lung cancer (NSCLC) patients. Therefore, we investigated associations of 16,378 common single-nucleotide polymorphisms (SNPs) in 97 methionine-metabolic pathway genes with overall survival (OS) in NSCLC patients using genotyping data from two published genome-wide association study (GWAS) datasets. In the single-locus analysis, 1,005 SNPs were significantly associated with NSCLC OS (P < 0.05 and false-positive report probability < 0.2) in the discovery dataset. Three SNPs (RUNX3 rs7553295G>T, AMD1 rs1279590G>A and MSRA rs73534533C>A) were replicated in the validation dataset and their meta-analysis showed that adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and Pmeta =2.86 x 10-6 , 0.81 (0.73-0.91) and Pmeta =4.63 x 10-4 , and 0.77 (0.68-0.89) and Pmeta =2.07 x 10-4 , respectively). A genetics score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (Ptrend <.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between these genotypes and gene mRNA expression levels. Moreover, differential expression analysis further supported a tumor-suppressive effect of MSRA, with lower mRNA levels in both lung squamous carcinoma and adenocarcinoma (P <.0001 and <.0001, respectively) than in adjacent normal tissues. Additionally, low mutation rates of these three genes indicated the critical roles of these functional SNPs in cancer progression. Taken together, these genetic variants of methionine-metabolic pathway genes may be promising predictors of survival in NSCLC patients. This article is protected by copyright. All rights reserved.
dc.language eng
dc.relation.ispartof International journal of cancer
dc.relation.isversionof 10.1002/ijc.32128
dc.subject Genome-wide association study
dc.subject Methionine
dc.subject Non-small cell lung cancer
dc.subject Single-nucleotide polymorphism
dc.subject Survival
dc.title Genetic Variants in RUNX3, AMD1 and MSRA in the Methionine Metabolic Pathway and Survival in Non-small Cell Lung Cancer Patients.
dc.type Journal article
dc.date.updated 2019-02-01T14:40:24Z
pubs.organisational-group School of Medicine
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Community and Family Medicine, Prevention Research
pubs.organisational-group Community and Family Medicine
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke Clinical Research Institute
pubs.organisational-group Biostatistics & Bioinformatics
pubs.organisational-group Basic Science Departments
pubs.organisational-group Population Health Sciences
pubs.organisational-group Medicine, Medical Oncology
pubs.organisational-group Medicine
pubs.publication-status Published
duke.contributor.orcid Luo, Sheng|0000-0003-4214-5809
duke.contributor.orcid Wei, Qingyi|0000-0002-3845-9445


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